With the latest major Phase 3 failure of Biogen and Eisai’s beta-amyloid-targeting antibody drug aducanumab, researchers are increasingly turning to other drug targets for Alzheimer’s disease.
“The absence of new drug approvals since 2003 and a rapidly growing prevalence of Alzheimer’s disease has created a ‘perfect storm’,” Charles Stacey, the CEO of Cerecin (formerly Accera), a healthcare company developing a drug for Alzheimer’s against a non-amyloid target, told BioSpace. “The high failure rate in Alzheimer’s disease has in part been due to a monocular focus on a single target, amyloid, and pharma companies prematurely progressing drugs to Phase 3 in the hope of expediting drug development.”
Part of the problem with developing Alzheimer’s drugs has also been that the disease is still not well understood. What is known is that problems with cellular functions and/or improperly functioning proteins cause brain cells, called neurons, to become damaged, leading to their decreased function and eventually death. This ultimately presents itself as memory loss symptoms in Alzheimer’s patients.
Although the toxic buildup of beta-amyloid and tau proteins has been the main focus of drug development in the hopes that getting rid of these proteins will prevent or reverse Alzheimer’s symptoms, there are other possible drug targets. One strategy takes a different approach by addressing the deficient metabolism in the brains of Alzheimer’s disease patients.
Brain metabolism and Alzheimer’s disease
The brain mainly uses glucose as its fuel, but in times when glucose is limited or not available (during starvation, fasting, or while on a low-carb diet, like the ketogenic diet), the brain can utilize a secondary source of energy called ketone bodies. Ketone bodies are small molecules created from breaking down fat (specifically fatty acids) in the liver. This alternative fuel source is meant to ensure the brain’s metabolism, and function, is maintained even in times of low glucose (or carbohydrate) intake.
As the physiological back-up fuel for the brain, ketone bodies can also support the metabolic needs of brains that cannot utilize glucose efficiently, such as in the brains of Alzheimer’spatients. Many years before symptoms appear, patients with Alzheimer’s show decreased glucose metabolism in certain areas of the brain that are involved in processing memories, including the parietal and temporal lobes. Region-specific decreased glucose metabolism is one of the earliest clinical markers detected in those at risk for Alzheimer’s disease and is recognized as a clinical feature of the disease that can be seen on brain scans.
What if we addressed this defective glucose metabolism by supplementing the brain an energy source it can effectively use (ketone bodies) – would this address or even prevent the symptoms of Alzheimer’s?
Testing the ketosis strategy: the ketogenic diet vs. dietary supplements
“Function of the brain is so critical for human life that it has a highly conserved back-up energy system – the majority of the time, the brain is fueled by glucose, but when food, and therefore glucose, is not available, it can also use ketone bodies,” commented Stacey. “At Cerecin, we asked a simple question: if an Alzheimer’s patients’ brain has difficulty metabolizing glucose, could it use this secondary fuel source of ketone bodies?”
Ketosis, or the state of having ketone bodies in the bloodstream (indicating their use as a partial energy source for the body), can be induced in a few ways: by fasting, which causes the body to run out of useable glucose and switch to breaking down fat for energy; by following a strict ketogenic or Atkins (high fat, low carb) diet, which leads to consistently ingesting a high concentration of fats that are broken down into ketone bodies by the liver; or by taking a ketogenic supplement, typically medium-chain triglycerides in the form of an oil.
The idea that diet- or supplement-induced ketosis may be able to help cognition and brain function in Alzheimer’s patients began gaining speed recently. At the 2017 Alzheimer’s Association International Conference (AAIC), there was an entire section of presentations about preliminary clinical results focusing on brain ketone metabolism and ketosis strategies. Some preliminary studies suggested that the brain can, in fact, use ketone bodies in lieu of glucose for energy. Other studies showed that the ketogenic diet can improve cognitive function in Alzheimer’s patients, medium-chain triglyceride supplements restored energy supply and slightly improved cognition in the brains of patients with mild cognitive impairment, and exercise increased ketone uptake in the brain.
In 2018, results from the first clinical trial testing the feasibility and preliminary cognitive effects of the ketogenic diet in Alzheimer’s patients. While this open-label pilot trial was very small (only 15 participants total) and had no controls, it indicated that the diet improved cognition in seven very mild and four mild Alzheimer’s patients, but was not successfully useful in moderate Alzheimer’s patients, as all four moderate patients (and one very mild patient) withdrew from the study due to caregiver burden. Patients had to follow a ketogenic diet and take medium-chain triglyceride supplements for three months, followed by a 1-month washout period where the patients resumed their normal diet. All 10 patients who completed the study achieved ketosis, as determined by blood analysis.
Patients were assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale test (ADAS-Cog), the “gold standard” set of tests used to assess cognition, especially language and memory, in Alzheimer’s patients. Patients who followed the diet showed an average of a 4.1-point improvement in cognition compared to baseline, where a 4-point improvement from baseline is clinically meaningful. These improvements were reduced after the 1-month washout period.
The same group is getting ready to launch another randomized, single-blind study where the ketogenic diet (70% fat, <10% carbs, and 20% protein) and the “therapeutic lifestyle changes” diet (20-35% fat, 50-60% carbs, and 15% protein) will be evaluated in 80 patients with Alzheimer’s disease. This study is estimated to begin this month.
While the ketogenic diet has been shown to improve cognition in mild Alzheimer’s patients, it is very difficult to stick to, especially for Alzheimer’s patients, whose tastes shift to prefer sweet, carbohydrate-rich foods. As caregivers know, finding foods Alzheimer’s patients will eat can be tricky, let alone having them follow a strict diet.
Cerecin’s ketogenic drug approach
Now, Cerecin is developing proprietary products that emulate the effects of a medium-chain triglyceride oil supplement by inducing a state of ketosis. This takes advantage of the benefits of mild chronic ketosis on brain activity and function without the strict limitations of following a ketogenic diet. Their products were inspired by a specialized type of medium-chain triglyceride, called caprylic triglyceride, which gets broken down by the liver into ketone bodies. These ketone bodies then travel to the brain and act as the brain’s fuel source.
In a Phase 2 trial involving 152 mild to moderate Alzheimer’s patients, patients with a specific genetic profile who consumed caprylic triglyceride daily showed significantly improved cognition and function versus those that consumed a placebo over a 90-day period.
Excitingly, patients receiving caprylic triglyceride showed a significant improvement in cognition as early as 45 days into treatment. Stacey explained why such a rapid response was seen: “Our mechanism relies on cellular energetics, providing an energy substrate that ‘switches’ brain cells ‘on’ – much like a car with an engine that lacks gas, providing gas would allow the car to quickly turn on again.”
Patients were assessed using the ADAS-Cog test. On day 45, all patients receiving caprylic triglyceride had a 1.9- to 2.6-point improvement in their score (remember, a 4-point improvement is clinically relevant). Interestingly, more improved cognition was seen in patients who did not have the APOE4 gene: ranging from 4.77- to 6.26-point score improvements at day 45 and 3.36- to 5.33-point score improvements at day 90.
All APOE genes encode a form of apolipoprotein E, a protein that combines with fats to form lipoproteins, which package and carry cholesterol and other fats through the bloodstream. The most common version of the gene is APOE3, which is found in over half the general population, does not appear to affect the risk of Alzheimer’s. The APOE4 version is famous for being linked to an increased risk of developing late-onset Alzheimer’s (the most common form of Alzheimer’s) and causing earlier-onset memory loss compared to those who don’t have the APOE4 gene. However, not all Alzheimer’s patients carry the APOE4 gene and not all people with the APOE4 gene will develop Alzheimer’s.
Cerecin has continued studying the efficacy of caprylic triglyceride-based drugs in non-APOE4carriers, as caprylic triglyceride was the most effective in this population despite all patients (with or without the APOE4 gene) showing significantly increased blood ketone body levels two hours after consuming caprylic triglyceride. Although it is not completely understood why cognition was improved only in this population, these findings have been replicated by other groups.
“The APOE4 protein is known to block part of the metabolic energy pathway, so if there is an APOE4-induced block in metabolism downstream of where ketone bodies provide energy, then brain metabolism would not be restored in patients with the APOE4 gene,” Stacey explained.
Cerecin’s lead drug compound, Tricaprilin, is a proprietary pharmaceutical formulation of caprylic triglyceride. The active ingredient of this drug is generally recognized as safe (GRAS) by the FDA, taken orally, and well-tolerated, which are all key to developing a drug for long-term use.
